Nitrosoamines

ABSTRACT

A SERIES OF NITROSOAMINES WHICH COMPRISE 4-N-NITROSON-ALKYLAMINOBENZYLIDENE DERIVATIVES OF A FUSED BICYCLIC MOIETY SELECTED FROM 1-INDENE, 2-METHYL QUINOLINE, 4-METHYL QUINOLINE, AND 1-METHYL ISOQUINOLINE. IN CONTRAST TO THE CARCINOGENIC ACTIVITY EXEMPLIFIED BY RELATED NITROSO AND AMINO COMPOUNDS, MEMBERS OF THE PRESENT GROUP OF NITROSO COMPOUNDS HAVE EXHIBITED CARCINOSTATIC ACTIVITY IN ANIMALS IN STANDARD TESTS AGAINST WALKER 256 TUMOR.

Patented Jan. 25, 1972 grouping is limited to a C -C variety. Preferred species are methyl and ethyl, and the carcinostatic activity varies inversely with the molecular weight of the substituent and dies out above C The N-aromatic fraction is characterized by an ethyl- 3,637,677 NITROSOAMINES Carl T. Bahner, David H. Brotherton, and Mary K.

Brotherton, Jelferson City, Tenn., assignors to the 5 United States of America as represented by the Secretary of the Department of Health, Education, and linkage l? i the aminp monoaryl and su.ch may be Welfare achieved by utilizing the ammostyryl or benzyhdene con- No Drawing. Filed Feb. 14, 1969, Ser. No. 799,505 figuration. Additionally, attached to the ethylene linkage I t, Cl, C07c 87/28; (107d 33/52 remote from the monoaryl, there is attached a fused bi- U.S. Cl. 260240.9 6 Claims 10 cyclic moiety selected from l-indene, Z-methyl quinoline,

4-methyl quinoline, and l-methyl isoquinoline. These compounds may be also alternatively viewed as 4-N-nitroso-N-alkylaminobenz lidene derivatives of a fused bic clic ABSTRACT OF THE DISCLOSURE moiety selected frorii l-indene, Z-methyl quinolind: 4- A series of nitrosoamines which comprise 4-N-nitrosomethyl quinoline, and y isoquinoline- N-alkylaminobenzylidene derivatives of a fused bicyclic N ARYL FRACTION VARIATION OF ACTIVITY moiety selected from 1-indene, Z-methyl quinoline, 4-meth- WITH STRUCTURE yl quinoline, and l-methyl isoquinoline.

In contrast to the carcinogenic activity exemplified by preferred Structure as to R2 is 4methyl quinoline related nitroso and amino compounds, members of the most Preferred P? are present group of nitroso compounds have exhibited carmethyl Nfmtrosoajmmobenzyhfiem?)lndene and (4N- cinostatic activity in animals in standard tests against methyl'N'mtrosoammosWW1)qulnohne- Walker 256 tumor. In Table I below the key column T/ C means the weight of tumor in test animal versus weight of tumor in control animal and indicates the efiicacy of the compounds in the testing. To be effective, a value of below .50 is arbi- TABLE I [Activity against Walker 256 Tumor using laboratory animals (Compounds 3,5,6 for comparison)] KB cell T or t. t Yield t t E U fli No, Compound percent 1! M.P., C. Formula" g./m1. mgJkg. T/C mgJkg. Killed -4 100 0.56 40 1 1-(4N-ethyl-N-nitroso-aminobenzyl- 53 123-124 C13H1N20 500 0,14 idene)indene. *1, 250 0. O8 1 1, 250 0/3 2 (4-N-ethyl-Nnitr0soaminostyryl) 59 120 5-1210 CNHUNHO x 10 -4 400 1/6 quincline. 4x200 0. 02 3 9-(4-N-Methyl-N-nitrosoaminobenzyl- 73 145-14 (3,1HNN20 100 "IX 90 X idene)fluorenel, 500 1 1 1, 500 0/3 0.15 1,500 3 4 1-(l-N-methyl-N-nitrosoaminobenzyl- 57 144-14 CHHHNzO 35 idene) indene. 600 07 4X400 0. 61 4x400 0/6 5 v -N- osoanunofiuore e- 51 120. 5422.0 CHHHNQO 4 0,8 .4X600 0/6 6 4-N-m thy1-N-mtrosoamm0stllbene 33 157 C15H14N2O 0,6 .4X400 0/6 :30 :25 75 0. 75 7 g g g fg N mtrosoemmostyrvl) 4 157 158 ClsHisNaO 66 g 3 4X1 000 0/6 n e 8 Additional material could be recovered from the mother liquors.

b Corrected for thermometer stem exposure; determine with Thiele tube.

a All compounds were analyzed for C, H. Analytical results obtained for those elements were within 10.3% of the theoretical values.

4 Results of the standard in vitro KB tumor cell inhlbltlon tests carried out under sponsorship of the Cancer Chemotherapy National Service Center at Southern Research Institute and A. D. Little Co.

C.C.N.S.C. made screening tests against Walker 256, using four daily injections beginning 3 days after tumor implant, carried out at Battelle Memorial Institute I Chester Beatty Research Institute achieved data on toxicity and activity against the Walker 256 tumor in rats weighing 200-250 g. NOTE.Each compound was administered as a single intraperitoneal injection in arachis oil on the day following tumor implantation or in the first day of the toxicity observation. Tumor bearing animals were sacrificed approximately 8 days later and the average weights of tumors in treated and untreated hosts are reported as the ratio T/G.

The present invention is directed towards a group of trarily given. It is noted that compounds 4 and 7 appar- N-nitrosoamines which are characterized by a lower alkyl ently gave superior results, and where the configuration substituent coupled with an aromatic substituent fulfilling of the molecule was changed, as in comparativ a particular structural configuration. Formulas showing pound 6 ith tilb and al o in compounds 3 and 5 the Strllfitllral Configuration fOf this group of Compounds 60 with fluorene, ineffective test data was achieved. The carare set out below: cinostatic activity of these compounds, selected members of which are shown above, is surprising in view of the Alkyl previous carcinogenic activity of nitrosoamines generally. Ary1. N (Cf. H. Druckrey, R. Preussmann, S. Ivanocic, and D.

Schmahl, Z. Krebsforsch, 69, 103 (1967.)

H GENERALIZED PROCESS FOR PREPARATION Rz=0- -N OF THE COMPOUNDS A stoichiometric amount of sodium nitrite was added to an acid alcoholic solution of the predetermined mono- The N-alkyl fraction is lower alkyl, and within that alkyl amine at a temperature 0-5 Water was added to 3 dissolve the sodium nitrite salt and the mixture was agitated and the product was crystallized. The yellow crystalline material obtained was recrystallized from oxygenated solvents; e.g., ethanol and isopropyl ether. Selected specific examples are given post.

AMINE REACTANTS The amine starting materials for preparing the compounds of the present invention are known and are described in one or more of the following publications by C. T. Bahner: Carl T. Bahner, J. Med. Chem. 8, 390, 1965, 1-(4-alkylaminobenzylidene)indene; J. Med. Chem. 7, 818, 1964, 4-(4-alkylaminostyryl)quinoline; J. Org. Chem. 27, 2233, 1962; and J. Org. Chem. 22, 683, 1957.

Additionally, it has been noted that 1-(4-N-methy1-N- nitrosoaminobenzyl)indane prepared by hydrogenation of 1-(4-N-nitrosoaminobenzylidene)indene and elimination of the ethylene structure from the molecule was ineffective against the Walker 256 tumor at 600 mg./kg. and only slightly elfective at 1500 mg./kg. with a T/C=0.60.

UTILITY STATEMENT The compounds of this invention have present utility in carcinostatic activity against Walker 256 tumor as shown by standard tests in animals.

EXAMPLES The following examples illustrate the working of this invention:

Example I 1- (4-N-methyl-N-nitrosoaminobenzylidene indene A magnetic stirrer was employed to dissolve 4.6 g. (.02 m.) of 1-(4-methylaminobenzylidene)indene in 200 ml. of absolute ethanol. After this solution was cooled to -5 C. in an ice bath, 5 ml. (11.7 molar)I-IC1 and then 1.4 g. of sodium nitrite and 5 ml. of water were added rapidly. The mixture turned from a dark orange to a lemon color after the addition of the HCl and sodium nitrite solution. The mixture was stirred during the cooling period above during the addition of HCl and sodium nitrite and also for an additional 2 hours. The solid was removed by 4 filtration and recrystallized from ethanol and isopropyl ether. The purified compound exhibited a melting point 144-46 C. and appeared as yellow plates.

Example II 4- (4-N-methyl-N-nitrosostyryl) quinoline In ml. absolute ethanol 10.4 g. (.04 m.) 4-(4-methylaminostyryl)quino1ine were dissolved using a magnetic stirrer. This solution was cooled to 0-5 C. Immediately 10 ml. (11.7 molar) HCl were added and followed rapidly with 10 ml. of water in which were dissolved 2.8 g. sodium nitrite. The mixture turned from a dark orange to a dark purple and finally a blood red color after the addition of the HCl-sodium nitrite solution. The reaction mixture was stirred for an additional 2 hours. The solid was removed by filtration and recrystallized from ethanol and isopropyl ether. The purified compound exhibited a melting point 157-58" C. and appeared as a yellow powder.

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A 4-N-nitroso-N-lower alkylaminobenzylidene derivative of a fused bicyclic moiety selected from the group consisting of 2-methyl quinoline, 4-methyl quinoline, and l-methyl isoquinoline.

2. A compound according to claim 1 wherein N-lower alkyl is C -C lower alkyl.

3. A compound according to claim 1 wherein the fused bicyclic moiety is 4-methyl quinoline.

4. A compound according to claim 1 wherein lower alkyl is methyl.

5. 4- 4-N-ethyl-N-nitrosoaminostyryl) quinoline.

6. 4- (4-NmethylN-nitrosoaminostyryl) quinoline References Cited Bahner et al., J. Med. Chem., vol. 11, pp. 401-2 (March 1968).

JOHN D. RANDOLPH, Primary Examiner US. Cl. X.R. 

